Although a relatively new technology in the pharmaceutical industry, hot-melt extrusion has been used in the production of many different dosage forms and systems. It has been demonstrated to be applicable to various dosage forms including granules, pellets, and tablets. It has also been shown to provide numerous advantages in the production of thin films for both drug delivery and wound care applications. New chemical entities that face poor bioavailability due to solubility issues together with These drugs and pharmaceutical devices encompass not only prescription products but over-the-counter products (OTC) as well. Hot-melt extrusion technologies offer numerous advantages over traditional methods. Shorter and more efficient processing times to a final product, environmental advantages due to elimination of solvents in processing (including the possibility of recycling), and increased efficiency of drug delivery to the patient.
Thin films for transdermal/transmucosal (TD/TM) drug delivery devices and wound care applications are frequently produced via film casting utilizing organic or aqueous solvents. Aitken-Nichol, et al. (Pharm. Res., 13:804-808 (1996); the entire disclosure of which is hereby incorporated by reference) noted numerous disadvantages accompanying these techniques including long processing times, high costs, and environmental concern. Gutierrez-Rocca, et al. (DDIP., 19:315-332 (1993); the entire disclosure of which is hereby incorporated by reference) demonstrated that the attainment of stable mechanical properties might be as long as two months, which ultimately affects the rate of release of drugs incorporated into the films. In addition, moisture permeability and moisture uptake of TD/TM films may affect sustained drug release as well as adhesion of the films to the epidermis or mucosa. Hjartstam, et al. reported that alterations in cellulose film structure influenced both drug transport and the mechanical properties of the film. Also, levels and types of plasticizers, temperature, and relative humidity have been demonstrated to affect the physical-mechanical properties and the dissolution rate of drugs through films formed from aqueous dispersions.
Films comprising pure hydroxypropylcellulose (HPC) and other water-soluble or water-swellable polymers cannot be readily produced by hot-melt extrusion due to the high stress that is exhibited on the extruder. Therefore plasticizers have been added to the HPC and other polymers as described below.
U.S. Pat. No. RE 33,093 to Schiraldi et al. (the entire disclosure of which is hereby incorporated by reference) describes a bioadhesive hot-melt extruded film for intra-oral drug delivery and the processing thereof. The film of Schiraldi et al. comprises essentially a bioadhesive layer consisting of 40-95% by weight of a hydroxypropylcellulose (HPC), 5-60% of a homopolymer of ethylene oxide (PEO), 0-10% of a water-insoluble polymer, a medicament and 2-10% of a plasticizer. The film was made by a hot-melt extrusion process. Mooney, et al. (U.S. Pat. No. 6,072,100; the entire disclosure of which is hereby incorporated by reference) also describes a medicament delivery system consisting of HPC, PEO, a water-soluble polymer derived from acrylic acid, a medicament and a plasticizer. In this system, the compositions were intended for topical or transdermal delivery only. Note, however, that both of these references disclose that a plasticizer is needed for the production of a hot-melt extruded film.
It should be noted that there are numerous disadvantages to utilizing a plasticizer in hot-melt extruded films. Many plasticizers, such as those used by Mooney et al. are used are in liquid form, e.g., propylene glycol and glycerin. It is difficult to homogeneously disperse the plasticizer into a precursor composition prior to extrusion. Also, lower molecular weight plasticizers are unstable to high temperatures and may degrade or volatinize off during extrusion. Plasticizer stability is an issue as reported by Gutierrez-Rocca et al. and others. These plasticizers are generally very hygroscopic, which makes processing and packaging of films containing them problematic. This property of water absorption also may lead to drug degradation in that many drugs are susceptible to hydrolysis. Indeed, moisture in a hot-melt extruded film is extremely detrimental to the homogeneity and integrity of the film, in that film imperfections such as vacuoles from moisture evaporation during extrusion are incorporated. In general, a dry blend, without a plasticizer is extremely advantageous, eliminating or minimizing the problems discussed above.
Gurtler, et al. teaches the development of a bioadhesive ophthalmic insert. However, the ophthalmic insert requires the presences of a water-insoluble polymer. More importantly, however, the method of preparation and the thickness of the insert is different than the process and film claimed herein. The formation of a solid solution of the necessary medicament was carried out by Gurtler et al. using a solvent evaporation process. Also, when preparing an insert containing HPC and Carbopol 934P, the extrusion was carried out on a piston extruder requiring two successive extrusions to produce rods, 5 mm long (or thick) and 1.35 to 1.45 in diameter. Thus the thickness of the inserts is significantly greater than the thickness of the film claimed herein. Note that there was no need for Gurtler et al. to dry the ingredients used to form the inserts, since the inserts are rods and not films. In addition, when a solid solution of gentamycin was prepared by Gurtler et al. to form an ophthalmic insert, a three-step process was necessary, one of the steps of which included acetone evaporation. A solvent evaporation step is not included in the claimed process.
Accordingly, the prior art does not disclose that films comprising a major portion of HPC and other water-soluble or water-swellable polymers can be produced by hot-melt extrusion in the absence of a plasticizer. However, hot-melt extrusion possesses many processing advantages useful in the pharmaceutical industries. Therefore, a need remains for a bioadhesive hot-melt extruded film that does not contain a plasticizer.
The present invention provides a bioadhesive extruded film that is an effective, feasible, and convenient topical or intra-cavity drug delivery system for applying and delivering controlled dosages of therapeutic agents onto the skin or into the body cavities. This invention may also be extended to controlled drug delivery in skin care or cosmetics, gynecological, vaginal, cranial, abdominal, otic, uterine, nasal, sinus, rectal, buccal, oral, ophthalmlc, and wound care applications and to adhesive applications, such as for use as a denture adhesive. The present hot-melt extrusion process generally provides shorter and more efficient processing times to a final product, environmental advantages due to elimination of solvents in processing, better stability due to the elimination of a plasticizer, and increased efficiency of drug delivery to the patient.
It has now been discovered that HPC containing from about 1-25% polycarbophil (Noveon AA-1) may be hot-melt extruded in the absence of a conventional plasticizer to increase bioadhesion.
This invention is generally directed to an extruded single or multi-layered laminated relatively thin film (1 to 120 mils, or 25 to 3000 microns in thickness) that can be cut or formed into almost unlimited shapes and sizes, depending on the application intended. Films of different thickness are prepared by changing the extrusion die, varying the extrusion rate or varying the film tension between the chill-roll or take-off roll and the extruder. Thinner films are formed by using narrower gauge dies and/or by increasing the tension between the rolls and the extruder.
The film generally comprises one or more water-soluble or water-swellable thermoplastic polymers such as hydroxypropylcellulose, polyethylene oxide, homopolymers and copolymers of carboxymethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose) with a medicament in the absence of a plasticizer. The hot-melt extruded film may also comprise about 1 to 25 percent by weight of a water-soluble or water-swellable polymer derived from acrylic acid or a pharmaceutically acceptable salt thereof, such as the polyacrylic acid polymers as follows: Polycarbophil (Noveon AA-1), carbomer (Carbopol 974P or 971P or 907), or a water-soluble salt of a co-polymer of methyl vinyl ether and maleic acid or anhydride (Gantrez MS-955). The film can also comprise one or more pH adjusting compounds, additives, and/or hydrophobic polymers that may render the film useful for particular applications. The film is generally used for local treatment (oral ulcer), non-local treatment (dental caries, central acting anesthetic, i.e. delivery of drugs through the oral mucosa), or for bioadhesive applications only (such as a denture adhesive in which the system would not necessarily contain a medicament).
The film formulations of the invention will adhere to mucosal surfaces (oral, rectal, vaginal, etc.) and/or skin surfaces when wet.
Accordingly, one aspect of the invention provides a composition for forming a hot-melt extruded film, the composition comprising:
about 30-95% wt. of one or more water-soluble or water-swellable thermoplastic polymers;
about 1-25% wt., or up to 25% wt., of polycarbophil;
about 1-60% wt., or up to 60% wt., of poly(ethylene oxide);
about 0.1-10% wt., or up to 10% wt., of an organic acid;
about 0.01-10% wt., or up to 10% wt., of an antioxidant; and
about 0-50% wt., or up to 50% wt., of a therapeutic agent; wherein the composition can be hot-melt extruded into a film without extensive degradation in the absence of a conventional plasticizer.
Another aspect of the invention provides a hot-melt extruded film comprising:
about 50-99% wt., or up to 99% wt., of one or more water-soluble or water-swellable thermoplastic polymer or polymers;
about 0-50% wt., or up to 50% wt., of a therapeutic agent; and
about 1-25% wt., or up to 25% wt., polycarbophil; wherein the film has been hot-melt extruded without extensive degradation in the absence of a conventional plasticizer.
Still another aspect of the invention provides a hot-melt extruded film comprising:
about 50-99% wt., or up to 99% wt., of one or more water-soluble or water-swellable thermoplastic polymer or polymers;
about 0-50% wt., or up to 50% wt., of a therapeutic agent; and
about 1-25% wt., or up to 25% wt., of a bioadhesive polymer selected from the group consisting of polycarbophil, carbopol, GANTREZ(copyright) (which is a co-polymer of methyl vinyl ether and maleic acid or anhydride), one or more acrylic polymers, one or more polyacrylic acids, copolymers of these polymers, a water soluble salt of a co-polymer of methyl vinyl ether and maleic acid or anhydride (Gantrez MS-955), a combination thereof and their salts, wherein the film has been hot-melt extruded without extensive degradation in the absence of a conventional plasticizer.
The invention also provides a process for preparing a hot-melt extruded film comprising the steps of:
providing a precursor composition comprising about 50-99% wt. of one or more water soluble or water swellable polymers, about 0-50% wt., or up to 50% wt., of a therapeutic agent; and about 1-25% wt., or up to 25% wt., of a bioadhesive polymer; and
hot-melt extruding the precursor composition to form a film;
wherein the precursor composition is hot-melt extruded without extensive degradation in the absence of a plasticizer.
Preferred embodiments of the invention include those wherein: 1) the film comprises a therapeutic agent; 2) the film is a denture adhesive when wetted with an aqueous solution or oral fluids; 3) the film is adapted for controlled delivery of a therapeutic agent to the buccal, oral, rectal, vaginal, abdominal, cranial, ophthalmic or otic cavities; 4) the extruded film is granulated and/or pulverized for use as a powder type adhesive; 5) the film comprises one or more pH adjusting agents; 6) the hot-melt extruded thin film is cut to a specific size and/or shape, especially prior to use as a denture adhesive; 7) the film comprises one or more film modifiers; 8) the film comprises a single layer; 9) the film comprises two or more layers; 10) the film comprises a super-disintegrant or super-absorbent; 11) the film contains a polyacrylic acid; 12) the film contains a water-insoluble polymer; 13) the composition, film and/or one or more thermoplastic polymers contain less than 2% wt. water, more preferably less than 1% wt. water, or most preferably less than 0.5% wt. water; 14) the film is about 1-120 mils, or about 25-3000 microns, thick; 15) the film includes one or more water insoluble polymers; 16) a buffering agent is present in an amount ranging from about 0.1-7.5% wt. or up to about 7.5% wt.; and/or 17) a preservative is present in an amount ranging from about 0.01-0.5% wt., about 0.02-0.2% wt., or up to about 0.5% wt.